RGD Reference Report - Fetal ethanol exposure activates protein kinase A and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly. - Rat Genome Database

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Fetal ethanol exposure activates protein kinase A and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly.

Authors: Aoto, Kazushi  Shikata, Yayoi  Higashiyama, Daisuke  Shiota, Kohei  Motoyama, Jun 
Citation: Aoto K, etal., Birth Defects Res A Clin Mol Teratol. 2008 Apr;82(4):224-31. doi: 10.1002/bdra.20447.
RGD ID: 12801437
Pubmed: PMID:18338389   (View Abstract at PubMed)
DOI: DOI:10.1002/bdra.20447   (Journal Full-text)


BACKGROUND: In humans, fetal ethanol exposure can cause holoprosencephaly (HPE), one of the most common birth defects that is characterized by brain, facial, and oral abnormalities. However, the pathogenesis of HPE is not clear. In the present study, we investigated the teratogenic mechanism of ethanol-induced brain and facial malformations in mice.
METHODS: Pregnant C57BL/6J mice were administered ethanol on E7 and facial and brain malformations were characterized on E10.5. We examined the effect of fetal ethanol exposure on Shh expression and activation of protein kinase A (PKA) because mutations in the human Shh gene are the most frequent cause of autosomal-dominant inherited HPE and PKA is a potent endogenous antagonist of Shh signaling.
RESULTS: Fetal ethanol exposure on E7 induced severe midline defects characteristic of HPE. Ethanol exposure impaired Shh expression and induced excessive apoptosis only along the anterior edge of the prechordal mesendoderm (PME). In addition, ethanol activated PKA in anterior PME cells. Pretreatment of embryos with antioxidants, such as vitamins C or E, prevented the development of ethanol-induced HPE.
CONCLUSIONS: Shh expression in PME cells is involved in the pathogenesis of ethanol-induced HPE. Ethanol may impair Shh expression indirectly by activating PKA. The inhibition of excessive apoptosis in PME cells by antioxidants implies that oxidative stress may underlie the teratogenic actions of ethanol. Thus, antioxidant treatment may be a simple preventative measure that could reduce the incidence of HPE following fetal ethanol exposure.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
holoprosencephaly  ISOCreb1 (Mus musculus)12801437; 12801437protein:increased localization: prechordal mesoderm and nucleusRGD 
holoprosencephaly  IEP 12801437protein:increased localization: prechordal mesoderm and nucleusRGD 
holoprosencephaly treatmentISOShh (Mus musculus)12801437; 12801437 RGD 
holoprosencephaly treatmentIEP 12801437 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Creb1  (cAMP responsive element binding protein 1)
Shh  (sonic hedgehog signaling molecule)

Genes (Mus musculus)
Creb1  (cAMP responsive element binding protein 1)
Shh  (sonic hedgehog)

Genes (Homo sapiens)
CREB1  (cAMP responsive element binding protein 1)
SHH  (sonic hedgehog signaling molecule)


Additional Information